The natriuretic peptides (NPS) include ANP, BNP and CNP. The NPS mediate their actions via generation of the second messenger cGMP following activation of biological receptors. We reported that NPS have different vasorelaxing actions in human internal mammary arteries (IMA) and saphenous veins (SV). Specifically, ANP is an arterial vasodilator and CNP is a specific venodilator. It is now well established that coronary artery bypass grafts (CABG) utilizing IMA have a greater patency rate than SV grafts. However, the mechanisms of this difference remain unclear. One could speculate that this difference may be due to the different actions of NPS in vascular smooth muscle cells (VSMC) of IMA as compared with SV. Apoptosis plays an important role during development of VSMC proliferation. Regulation of apoptosis involves a number of genes that include effectors such as p53 and p21-WAF, and genes that primarily suppress apoptosis, such as bcl-2 gene family. Our prelimary data indicated that NPS induces apoptosis in human VSMC associated with increasing p53. Therefore, the hypothesis of this application is that the NPS induces apoptosis through the process involving the p53 gene in VSMC. The apoptotic effects of NPS may differ in isolated human VSMC from IMA as compared with SV. Furthermore, inhibition and activation of the cGMP pathway may alter NPS-mediated apoptosis and p53 gene expression in VSMC. This project will focus on the following Specific Aims: Aim 1. To determine the apoptotic effect of NPS in VSMC isolated from human IMA and SV. Aim 2. To determine the p53 gene expression during NPS-induced apoptosis in VSMC isolated from human IMA and SV. Aim 3. To determine the effects of inhibition and activation of the cGMP pathway on NPS-induced apoptosis and the p53 gene expression in VSMC isolated from human IMA and SV. Aim 4. To determine the relationship of the p53 gene with p21-WAF gene and bcl-2 gene expression during NPS-induced apoptosis in VSMC isolated from IMA and SV.